For the healthy daughters and sisters of the 200,000+ women diagnosed with breast cancer each year in the U.S., the threat of this disease is particularly salient. Biologically, they are at risk for carrying genes that increase their likelihood of developing breast cancer. Even after accounting for BRCA1/2, women with breast cancer in their families (FH+) have at least twice the population risk. Psychologically, they are at risk for symptoms of anxiety, depression, and posttraumatic stress, even years after the diagnosis. An understudied possibility is that these women may also have heightened hypothalamic pituitary adrenal (HPA) axis (e.g., cortisol) responses to acute stress, a major pathway by which stress can affect health. The contributions of genetic and/or psychological factors to this heightened responsivity have not been investigated. The overall goal of the proposed research is to test the hypothesis that healthy women with family histories of breast cancer have heightened HPA axis stress responsivity, and to investigate the contributions of the genetic and psychological aspects of family histories to response variability. Healthy, FH+, premenopausal, working women and a frequency matched FH- sample will be recruited. After rigorous prescreening to reduce extraneous sources of variability, HPA axis stress responsivity will be evaluated in two well-established, tightly-controlled, stress paradigms: 1) a laboratory approach, the Trier Social Stress Test (high internal validity); and, 2) a 'real world' approach, work-stress in daily life (high external validity). Combined results of these approaches will be statistically examined (n=220 with complete data) to explore a broader model of family history effects on stress responsivity. Research aims of this psychobiological study are: 1) to investigate the relationship between family history of breast cancer and women's HPA axis responses to stress under controlled laboratory conditions; 2) to examine the relationship between family history of breast cancer and women's cortisol responses to stress under naturalistic conditions; 3) to evaluate the effects of genetic risk and psychological sequelae of having a family history of breast cancer on women's cortisol responses to stress under laboratory and naturalistic conditions, using structural equation analyses of combined data. PUBLIC HEALTH RELEVANCE: If the results of the proposed research indicate a significant contribution of the genetic aspects of family history to heightened HPA axis responsivity to stress, it would raise the possibility that inherited predispositions to responsivity in these women could be a contributing mechanism for their increased risk of developing breast cancer and would open up a new area of research into the etiology of this disease that is diagnosed in more than 200,000 American women each year. If the results of the proposed research indicate a significant contribution of the psychological sequelae of having a family history of breast cancer to heightened HPA axis responsivity, it would suggest that the experience of breast cancer in a close relative may have biologically significant consequences for years after their relative was diagnosed with cancer and would open up a new area of research into the broader health consequences of this increased responsivity.